The circulating T lymphocyte pool contains multiple antigen-experienced subpopulations bearing distinct tissue tropisms. The two best understood types are those associated with the skin or the intestine. Each subset is responsible for immunological memory and surveillance of its own target tissue. The evolutionary purpose for this strict "division of labor" remains debatable. However, an improvement in our understanding of this phenomenon, particularly at the molecular level, will undoubtedly inspire new strategies to treat and prevent human disease. The concept of tissue-specific lymphocyte tropism must be considered when designing efficient vaccination strategies, and when developing new approaches to treat organ-specific autoimmune disorders. Naive T cells do not have the ability to home to non-lymphoid organs such as skin. This ability is gained after exposure to skin-derived antigen within cutaneous lymph nodes. This process occurs when antigen-presenting cells (primarily dendritic cells) take up antigen from inflamed skin for display on cell-surface MHC molecules. Most changes that occur to naive T cells in response to antigen (such as clonal proliferation, loss of naive markers, and gain of activation/effector/memory markers) can occur within any given lymphoid organ. However, induction of the E-selectin ligand and the chemokine receptor CCR4 (molecules required for homing to inflamed skin) is unique to the dendritic cells within cutaneous lymph nodes. Interestingly, our preliminary data suggests that only a subset of antigen-responsive naive T cells express skin-specific homing markers within inflamed cutaneous lymph nodes. We hypothesize that only a specific subpopulation of dendritic cells found within cutaneous lymph nodes can induce T cell expression of skin homing molecules. We propose 1) to design a model for loading dendritic cells with antigen from inflamed skin in vivo to induce differentiation of naive T cells into skin- homing cells in vitro;and 2) to use this model to determine which of the eight or more identifiable dendritic cell populations within cutaneous nodes have the ability to trigger this skin-specific differentiation program. PUBLIC HEALTH RELEVANCE: The skin is one of the major physical barriers protecting an organism from disease- causing agents in the outside world, and the immune systems of humans and other mammals contain a specialized set of cells dedicated to patrolling this organ. Understanding how the immune system "remembers" antigens that have been previously encountered in the skin is an important consideration in developing vaccines for agents that attack through the skin, and in developing treatments for immune diseases that target the skin, such as psoriasis. Our project will help us to understand how immune cells develop the ability to enter the skin to repulse disease-causing agents.